Our goal is to identify drugs against a novel and unexploited target for the treatment of AIDS. The human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a complex retrovirus that encodes six regulatory proteins, including Vif that is essential for the production of infectious virions. We will focus our efforts on Vif as the target for drug discovery. Our specific aims are as follows: 1. To identify small molecules that bind to Vif by in vitro screening of a split-synthesis combinatorial library immobilized on solid bead supports (one compound per bead). Experiments are proposed to use high throughput screening methods for identification of ligands that can target Vif protein structure. 2. To test the individual compounds identified in the primary screen for in vitro binding to Vif. Biophysical methods will be developed to quantitatively determine the binding affinities of small molecules to Vif protein. 3. To assay the in vivo activities of Vif ligands. The compounds selected from in vitro screens will be tested for their anti-HIV activity in both permissive and non-permissive cells. The properties of the lead compounds can be optimized and improved by analyzing the structure-function relationships governing inhibition of Vif function and target selectivity. These pharmacological probes of Vif function can provide important new insights into HIV biology.